Project Summary During development, learning or progression towards disease, the brain undergoes plastic changes characterized by gradual increases or decreases in synaptic transmission. Modeling such changes by artificial means is necessary for understanding their functional role. Recently developed optogenetic and chemogenetic techniques allow neuronal activation or suppression, but they act in the all-or-none manner and do not allow modeling of gradual synaptic changes. Meanwhile, such gradual changes can be obtained by inducing long-term potentiation (LTP) or depression, but these techniques do not work reliably in all areas of the brain, particularly in the areas with a strong inhibitory control, which include the basolateral amygdala. In the pilot experiments, we found that a transient chemogenetic or optogenetic suppression of the somatostatin- but not parvalbumin-positive interneurons enables LTP induction in the prefrontal- amygdala pathway. Based on these findings and published data, we hypothesize that a transient suppression of certain classes of the local GABAergic neurons, combined with stimulation of synapses of interest, will provide a universal means for inducing LTP in the remote inputs to the local principal neurons in vivo. We will test this hypothesis in Aim 1 using the prefrontal-amygdala circuit, because its artificial synaptic modulation has been especially difficult to achieve, while the need for such modulation is high given the role of this circuit in the behavioral traits relevant to mental disease. In Aim 2, we will test predictions that synaptic efficacy in the dmPFC-BLA loop determines oscillatory synchronization between the two structures and influences anxiety- like behaviors. These predictions are based on findings that theta oscillations synchrony between BLA and dmPFC increase with innate anxiety in the open field, and photostimulation of BLA axonal terminals in dmPFC acutely increase anxiety-like behaviors in the elevated plus maze and open field. The study is expected to produce techniques for obtaining LTP of a desirable magnitude in glutamatergic synapses connecting principal neurons of dmPFC and BLA. The classes of GABAergic neurons that gate LTP in these pathways will be identified, and methods for their transient suppression to aid LTP induction will be developed. This LTP optimization process will provide a template for developing analogous LTP protocols for other brain areas. The role of synaptic efficacy of the dmPFC-BLA reciprocal projections in oscillatory synchronization and anxiety-relevant traits will be determined, which will inform about potential methods for targeted manipulation of that pathway in emotional disorders.